title: Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy.
abstract: X-linked adrenoleukodystrophy is a neurometabolic disorder caused by inactivation of the peroxisomal ABCD1 transporter of very long-chain fatty acids. In mice, ABCD1 loss causes late onset axonal degeneration in the spinal cord in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. Increasing evidence indicates that oxidative stress and bioenergetic failure play major roles in the pathogenesis of X-linked adrenoleukodystrophy. In this study, we aimed to evaluate whether mitochondrial biogenesis is affected in X-linked adrenoleukodystrophy. We demonstrated that Abcd1 null mice show reduced mitochondrial DNA concomitant with downregulation of mitochondrial biogenesis pathway driven by PGC-1α/PPARγ and reduced expression of mitochondrial proteins cytochrome c, NDUFB8 and VDAC. Moreover, we show that the oral administration of pioglitazone, an agonist of PPARγ, restored mitochondrial content and expression of master regulators of biogenesis, neutralized oxidative damage to proteins and DNA, and reversed bioenergetic failure in terms of ATP levels, NAD+/NADH ratios, pyruvate kinase and glutathione reductase activities. Most importantly, the treatment halted locomotor disability and axonal damage in X-linked adrenoleukodystrophy mice. These results lend support to the use of pioglitazone in clinical trials with patients with adrenomyeloneuropathy and reveal novel molecular mechanisms of action of pioglitazone in neurodegeneration. Future studies should address the effects of this anti-diabetic drug on other axonopathies in which oxidative stress and mitochondrial dysfunction are contributing factors.
authors.affiliation: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Morató
authors.forename: Jorge
authors.initials: J
authors.lastname: Galino
authors.forename: Montserrat
authors.initials: M
authors.lastname: Ruiz
authors.forename: Noel Ylagan
authors.initials: NY
authors.lastname: Calingasan
authors.forename: Anatoly A
authors.initials: AA
authors.lastname: Starkov
authors.forename: Magali
authors.initials: M
authors.lastname: Dumont
authors.forename: Alba
authors.initials: A
authors.lastname: Naudí
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Martínez
authors.forename: Patrick
authors.initials: P
authors.lastname: Aubourg
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otín
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.forename: Elena
authors.initials: E
authors.lastname: Galea
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fourcade
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000326:Adrenoleukodystrophy / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C552836:Abcd1 protein, mouse; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D005980:Glutathione Reductase; D000077205:Pioglitazone
keywords: X-linked adrenoleukodystrophy; axonal degeneration; mitochondrial biogenesis; oxidative stress; pioglitazone